There is intense interest in the concept that prolongation of cardiac repolarization may be an important mechanism whereby drugs suppress arrhythmias. However, marked repolarization increases have also been associated with induction of arrhythmias. Our initial clinical and in vitro studies of this arrhythmia- provoking action demonstrated that long cycle lengths and low extracellular potassium markedly potentiated the repolarization- prolonging effect of quinidine; under these conditions, a distinctive polymorphic ventricular tachycardia (Torsades de Pointes) developed in patients and early after depolarizations (EADS) were elicited in canine Purkinje fibers. In the previous period of support, studies were conducted to further evaluate our working hypothesis that EADs are linked to the genesis of Torsades de Pointes. One of the most important findings to date is that ventricular muscle blunts the action potential prolongation and EAD induction by quinidine in Purkinje tissue. We will now further examine the impact of modulation of Purkinje-ventricular coupling by interventions such as altered Cai (e.g. digitalis) and Cao, drugs (quinidine, amiodarone) and medium chain alcohols. We have implemented a computer model of porpagating Purkinje and ventricular muscle action potentials liked with variable axial resistivities in a one-dimensional cable which will be refined in parallel with experimental results. In this way, the hypothesis that EADs cause arrhythmias in vivo will be further tested and conditions which are important for the genesis or suppression of EAD-mediated arrhythmias identified. Despite increasing interest in the use of repolarization-prolonging drugs in the management of cardiac arrhythmias, little information is available on the ionic mechanism(s) whereby they exert this effect. In the past year we have accumulated evidence that the interaction of quinidine and amiodarone with the delayed rectifier IK (a repolarizing current) in voltage-clamped guinea pig ventricular myocytes is time- and voltage-dependent. These date suggest that drug effects on IK are modulated by the state of this potassium channel. A second major goal of the studies we now propose is to further test this hypothesis. We will initially characterize the effects of quinidine and amiodarone on IK as a function of initial channel state. Subsequently, we will examine the effects of these and other structurally related agents in other tissues (Purkinje, atrial). The results will not only characterize the impact of channel state on drug effect, but will also be used to quantify drug action in a multistate model of drug-channel interactions. Through this series of studies, therefore, we will increase our understanding of the fundamental mechanisms whereby drugs prolong repolarization and induce arrhythmias; in this way, the development and clinical use of repolarization- prolonging antiarrhythmic drugs will be improved.